The Xpert MTB/RIF assay, an automated, integrated nucleic acid amplification diagnostic test, has been a major breakthrough in tuberculosis (TB) diagnostics. Yet, large proportions of TB suspects are placed on TB treatment based on empirical decision-making even in settings where Xpert MTB/RIF is available. Empirical TB treatment decisions can be problematic, resulting both in under-treatment and in over-treatment. A major driver of empirical TB treatment is Xpert MTB/RIF?s modest sensitivity in smear-negative pulmonary TB patients ? Xpert MTB/RIF detects only about one-half to two-thirds of such patients. A TB test with exceedingly high sensitivity and negative predictive value would substantially increase clinicians? confidence in a negative test result and thereby shift therapeutic decision making away from empiricism and towards a microbiological evidence-based approach. To maximize the individual and population level impact of rapid TB diagnostics, the Xpert MTB/RIF assay has been re-engineered to substantially increase test sensitivity, as demonstrated by preliminary data. The proposed research will establish the clinical diagnostic accuracy of the new Ultra test in adults with signs/symptoms of pulmonary TB, and will provide information about the potential impact of Ultra-based diagnostic algorithms on individual and public health. Project aims are 1) to determine the clinical diagnostic accuracy of the Ultra test for detection of M. tuberculosis in sputum; 2) to refine estimates of Ultra specificity for detection of rifampin resistance; and 3) to characterize short-term participant outcomes including initiation of treatment and to model the potential health impact and cost-effectiveness of TB diagnosis using Ultra. Two hypotheses will be tested with regard to TB case detection ? first, that Ultra sensitivity is superior to that of Xpert MTB/RIF in adults with smear-negative/culture-confirmed pulmonary TB; and second, that the sensitivity of a single Ultra test is non-inferior to that of a single liquid culture in adults with pulmonary TB. To accomplish these aims, a multi-site clinical diagnostic accuracy study will be conducted in Uganda, Kenya, South Africa, and Brazil. This study will incorporate a robust gold standard of multiple sputum cultures at the time of a participant?s enrollment; an observational component comprised of follow-up over two months will allow characterization of treatment initiation patterns and collection of parameter estimates for mathematical models. This proposal will extend an ongoing early phase Ultra accuracy study currently being performed by the DMID/TB-Clinical Diagnostics Research Consortium in the same settings, and thereby accrue sufficient participants to test these novel hypotheses in a step-wise technology evaluation process that is seamless and efficient. Study results are expected to form the evidence base for World Health Organization policy guidance; a finding that Ultra sensitivity is non-inferior to that of a liquid culture test could transform TB diagnostic algorithms and clinical care.